A new serotonin 5-HT6 receptor antagonist with procognitive activity : importance of a halogen bond interaction to stabilize the binding
González-Vera, Juan A. (Universidad Complutense de Madrid. Departamento de Química Orgánica)
Medina, Rocio A. (Universidad Complutense de Madrid. Departamento de Química Orgánica)
Martín-Fontecha, Mar (Universidad Complutense de Madrid. Departamento de Química Orgánica)
Gonzalez, Angel (Universitat Autònoma de Barcelona. Laboratori de Medicina Computacional)
De La Fuente, Tania (Universidad Complutense de Madrid. Departamento de Química Orgánica)
Vázquez-Villa, Henar (Universidad Complutense de Madrid. Departamento de Química Orgánica)
García-Cárceles, Javier (Universidad Complutense de Madrid. Departamento de Química Orgánica)
Botta, Joaquín (University of East Anglia. School of Pharmacy (Norwich, Regene Unit))
McCormick, Peter J. (University of East Anglia. School of Pharmacy (Norwich, Regene Unit))
Benhamú, Bellinda (Universidad Complutense de Madrid. Departamento de Química Orgánica)
Pardo Carrasco, Leonardo (Universitat Autònoma de Barcelona. Laboratori de Medicina Computacional)
López-Rodríguez, Maria L. (Universidad Complutense de Madrid. Departamento de Química Orgánica)

Date:	2017
Abstract:	Serotonin 5-HT6 receptor has been proposed as a promising therapeutic target for cognition enhancement though the development of new antagonists is still needed to validate these molecules as a drug class for the treatment of Alzheimer's disease and other pathologies associated with memory deficiency. As part of our efforts to target the 5-HT6 receptor, new benzimidazole-based compounds have been designed and synthesized. Site-directed mutagenesis and homology models show the importance of a halogen bond interaction between a chlorine atom of the new class of 5-HT6 receptor antagonists identified herein and a backbone carbonyl group in transmembrane domain 4. In vitro pharmacological characterization of 5-HT6 receptor antagonist 7 indicates high affinity and selectivity over a panel of receptors including 5-HT2B subtype and hERG channel, which suggests no major cardiac issues. Compound 7 exhibited in vivo procognitive activity (1mg/kg, ip) in the novel object recognition task as a model of memory deficit.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	Scientific reports, Vol. 7 (2017) , art. 41293, ISSN 2045-2322

DOI: 10.1038/srep41293
PMID: 28117458

10 p, 1.2 MB

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